The cerebral cortex contains two types of neurons, excitatory projection neurons and inhibitory interneurons. Based on chemical, physiological and morphological criterion, the inhibitory interneurons occur in distinct subtypes that subserve distinct functions. Several common illnesses, including epilepsy and schizophrenia may involve the abnormal development and/or dysfunction of particular interneuron subtypes. The long-term objective of this research is to understand the molecular basis for interneuron subtype specification. Recent studies have determined that most cortical interneurons derive from the ventral forebrain, in the anlage of the basal ganglia. The Aims of this project are designed to investigate the following questions. Are the cortical interneurons fated to become specific subtypes within the ventral forebrain where they are born? Alternatively, (or in addition) do they migrate into the cortex as GABAergic "protointerneurons" that utilize local factors to determine their ultimate subtype? Aim 1: Regional and temporal influences on interneuron subtype specification. Two methods will be employed to examine whether distinct interneuron subtypes have distinct sources. First, cells from various cortical and subcortical regions of mouse telencephali, at various times over the age-range of cortical neurogenesis, will be transplanted into neonatal cortical environments in vivo and in vitro. The effect of the donor cell's place and time of birth on their differentiated fate will be assessed. Second, a transgenic mouse expressing the Cre-recombinase under control of the transcription factor Nkx2.1 under will be generated. This mouse will permit fate-mapping of cells that originated within a subregion of the subcortical telencephalon, the medial ganglionic eminence and preoptic area. Aim 2: Factors that specify cortical interneuron subtypes: A candidate molecule approach. Since preliminary evidence suggests that important aspects of interneuron subtype specification do occur in within the ventral telencephalon, a candidate molecule approach is being taken to study factors which may influence this process. The two main factors under investigation, by manipulations in slice cultures followed by transplantation, are the secreted signalling molecule Sonic Hedghog, and the transcription factor Lhx6.